The 2-chlorosulfinylazetidine-4-one compounds are valuable intermediates in the preparation of 3-exomethylene compounds which in turn are used in the manufacture of clinically useful antibacterial agents such as Cefaclor, Cefroxidine, etc. These intermediate compounds are conventionally prepared by the reaction of corresponding penicillin sulfoxide esters with N-chlorophthalimide in an inert organic solvent at 75.degree.-140.degree. C.
U.S. Pat. Nos. 4,052,387 (Oct. 4, 1977) and 4,081,440 (Nov. 28, 1978) by Kukolja describe a process for the preparation of 2-chlorosulfinylazetidine-4-one by treatment of the corresponding penicillin sulfoxide ester with an N-chlorohalogenating agent in an inert organic solvent in the presence or absence of a non-alkaline acid scavenger such as propylene oxide, butylene oxide, and the like, to remove any hydrogen chloride formed in the reaction. Cyclization of the intermediate with a Friedel-Craft's catalyst affords the corresponding 3-exomethylene cepham sulfoxide ester in an overall yield of 25-40% (with the exception of example 8 in U.S. Pat. No. 4,052,387).
Further, in U.S. Pat. No. 4,165,315 (Aug. 21, 1979), Kukolja describes a method similar to that of U.S. Pat. Nos. 4,052,387 and 4,081,440 for the preparation of 2-chlorosulfinyl-azetidine-4-one, by using a non-alkaline acid scavenger such as propylene oxide, which on cyclization with stannic chloride gives the 3-exomethylene compound in a very low yield (9-34%).
The methods described in the above patents do not provide an economical, commercially viable process when the reaction scale is increased beyond typical research quantities. For example, in those instances where a quantity of 50 gm or more of penicillin sulfoxide ester has been used as the starting material, the results are poor.
In U.S. Pat. Nos. 4,075,203 (Feb. 21, 1978) 4,165,316 (Aug. 27, 1979) Chou describes an improved process for the preparation of 2-chlorosulfinyl-azetidine-4-one intermediate by carrying out the reaction of penicillin sulfoxide ester with an N-chlorohalogenating agent in the presence of alkylene oxide in combination with calcium oxide as a hydrogen chloride acceptor. The intermediate on cyclization with a Lewis acid affords 3-exomethylene cepham ester with an overall yield varying between 32-59%.
Further improvement is reported in U.S. Pat. No. 4,289,695 (Sep. 15, 1981) by Chou wherein the use of a weakly basic, organic solvent insoluble, poly-4-(vinylpyridine) polymer cross linked with divinyl benzene as a hydrogen chloride binding agent has been used in the chlorinating step to give 2-chlorosulfinylazetidine-4-one which on cyclization with a Lewis acid gives the corresponding 3-exomethylene cepham sulfoxide esters.
A further improvement is reported in Indian Patent Application No. 1019/Del/89 (corresponding to U.S. Pat. No. 5,070,195) in which the use of a strongly basic ion exchange resin is described to scavenge liberated hydrogen chloride during the chlorinating step. The 2-chlorosulfinylazetidine-4-one produced by this method is cyclized using a Friedel-Craft's catalyst to afford 3-exomethylene cepham sulfoxide esters.
The present invention relates to an improved method for the preparation of 2-chlorosulfinylazetidine-4-one from penicillin sulfoxide ester. It relates to an improvement in the first step of a two step process for converting penicillin sulfoxide esters via 2-chlorosulfinylazetidine-4-one intermediates to 3-exomethylene sulfoxide esters.
According to this invention, it has been found that a substantially higher yield and purity of 3-exomethylene sulfoxide ester may be achieved when an inert, organic solvent insoluble, weakly basic N-alkali metal salt of cyclic imide is used to bind the hydrogen chloride formed in one of the side reactions during the first stage of the two step process, which first stage comprises the heating of a penicillin sulfoxide ester with an N-halogenating agent in an inert organic solvent at a temperature of about 75.degree. C. to 140.degree. C. to form 2-chlorosulfinyl-azetidine-4-one intermediate.
The use of these weakly basic N-alkali metal salt of cyclic imides effectively removes the hydrogen chloride from the reaction system and thus prevents the formation of degradation products, hence giving overall higher yields. At the end of the reaction, the insoluble inorganic salt of alkali metal and cyclic imide formed during the reaction of hydrogen chloride with weakly basic N-alkali salt of cyclic imide can be easily removed by filtration after cooling the reaction mixture to a desirable temperature.
An advantage of the present invention is that the weakly basic N-alkali metal salts of cyclic imide are inexpensive and can be easily prepared by known methods as compared to the expensive and troublesome methods of preparation of cross-linked polymers as reported in the prior art (e.g., U.S. Pat. No. 4,289,695 of Sep. 15, 1981), thus making the present invention more useful and simpler for industrial preparation.